The purpose of this project is to elucidate the neural mechanisms and principles of treatment of chronic pain syndromes, with particular attention to the drug treatment of pain caused by nerve injury. Current research is based on observations from animal studies and an initial clinical trial with ketamine that neuropathic pain may be largely mediated by CNS excitation of glutamate receptors. Based on the hypothesis that low affinity NMDA channel blockers which bind to the ion channel for only a fraction of a second will cause less impairment of normal CNS function, two clinical trials evaluated dextromethorphan in patients with diabetic neuropathy and post-herpetic neuralgia. Both studies showed that dextromethorphan reduces diabetic but not post-herpetic pain, indicating that chronic treatment with NMDA antagonists is reasonably well-tolerated and relieves pain. Animal studies suggest that another class of glutamate receptors - AMPA/kainate receptors - play a key role in pain perception and neural sensitization. A dose-response evaluation of an investigational AMPA/kainate antagonist in normal volunteers demonstrated a dose-limiting transient visual obscuration, presumably by blockade of these receptors in the visual system. The antagonist (LY293558) reduced pain and hyperalgesia caused by prior injection of intradermal capsaicin by approximately 50% at doses not producing side effects, but had no effect on the perception of thermal and electrical pain stimuli applied to normal skin. These results suggest that AMPA/kainate antagonists may have utility as analgesics in conditions that include a component of sensitization of central neurons.